The TNF-α/NF-κB signaling pathway has a key role in methamphetamine-induced blood-brain barrier dysfunction

J Cereb Blood Flow Metab. 2015 Aug;35(8):1260-71. doi: 10.1038/jcbfm.2015.59. Epub 2015 Apr 22.


Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Biological Transport / drug effects
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Central Nervous System Stimulants / adverse effects*
  • Central Nervous System Stimulants / pharmacology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Methamphetamine / adverse effects*
  • Methamphetamine / pharmacology
  • NF-kappa B / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Central Nervous System Stimulants
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Methamphetamine